TPX2 lactylation is required for the cell cycle regulation and hepatocellular carcinoma progression.

Targeting protein for Xklp2 (TPX2) is critical for mitosis and spindle assembly because of its control of Aurora kinase A (AURKA). However, the regulation of TPX2 activity and its subsequent effects on mitosis and cancer progression remain unclear. Here, we show that TPX2 is lactylated at K249 in hepatocellular carcinoma (HCC) tumour tissues and that this process is regulated by the lactylase CBP and the delactylase HDAC1. Lactate reduction via either shRNAs targeting lactate dehydrogenase A or the lactate dehydrogenase A inhibitor GSK2837808A decreases the level of TPX2 lactylation. Importantly, TPX2 lactylation is required for the cell cycle regulation and tumour growth. Mechanistically, TPX2 lactylation disrupts protein phosphatase 1 (PP1) binding to AURKA, enhances AURKA T288 phosphorylation, and facilitates the cell cycle progression. Overall, our study reveals a previously unappreciated role of TPX2 lactylation in regulating cell cycle progression and HCC tumorigenesis, exposing an important correlation between metabolic reprogramming and cell cycle regulation in HCC.